LOREEV XR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LOREEV XR (LOREEV XR).
Levetiracetam is a racetam anticonvulsant that binds to synaptic vesicle glycoprotein 2A (SV2A), reducing neurotransmitter release and neuronal excitability. It also inhibits N-type calcium channels and modulates GABAergic and glutamatergic transmission.
| Metabolism | Levetiracetam undergoes hydrolysis of the acetamide group via esterases in blood and tissues to an inactive carboxylic acid metabolite (ucb L057). It is not extensively metabolized by CYP450 enzymes. Approximately 66% is excreted unchanged in urine; 24% as ucb L057. |
| Excretion | Renal excretion of unchanged drug accounts for approximately 70% of elimination; fecal excretion accounts for approximately 30%, primarily as metabolites. |
| Half-life | Terminal elimination half-life is 6-8 hours in healthy adults; prolonged in renal impairment (up to 16 hours in severe impairment). |
| Protein binding | Approximately 35% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is 1.5-2.5 L/kg, indicating extensive extravascular distribution. |
| Bioavailability | Oral bioavailability is approximately 60-70% due to first-pass metabolism; extended-release formulation has similar bioavailability. |
| Onset of Action | Oral: 30-60 minutes to initial effect; peak plasma concentrations at 3-4 hours. |
| Duration of Action | Duration of clinical effect is 8-12 hours based on extended-release formulation. |
| Molecular Weight | Labetalol: 328.4 Da; Hydrochlorothiazide: 297.7 Da |
50 mg orally once daily, preferably in the evening. Maximum dose 100 mg/day.
| Dosage form | CAPSULE, EXTENDED RELEASE |
| Renal impairment | eGFR 15-29 mL/min: 25 mg orally once daily. eGFR <15 mL/min or on dialysis: not recommended. |
| Liver impairment | Child-Pugh class A: no adjustment. Child-Pugh class B or C: not recommended (no data). |
| Pediatric use | Not approved for pediatric patients <18 years. Safety and efficacy not established. |
| Geriatric use | No specific dose adjustment recommended based on age alone. Use caution due to increased sensitivity and potential for renal impairment; consider lower starting dose (25 mg) and titrate slowly. |
| 1st trimester | Avoid. LOREEV XR is a combination of labetalol and hydrochlorothiazide. First trimester use of thiazide diuretics is associated with increased risk of congenital anomalies, including neural tube defects and limb reductions. |
| 2nd trimester | Avoid. Thiazide diuretics can cause placental hypoperfusion, fetal growth restriction, and electrolyte disturbances. Labetalol may cause fetal bradycardia. |
| 3rd trimester | Avoid. Thiazide diuretics can cross the placenta and cause neonatal hypoglycemia, thrombocytopenia, and electrolyte abnormalities. Labetalol may cause prolonged fetal bradycardia and neonatal hypotension. |
Clinical note
Comprehensive clinical and safety monograph for LOREEV XR (LOREEV XR).
| Placental transfer | Both labetalol and hydrochlorothiazide cross the placenta. Labetalol reaches fetal concentrations approximately 50-80% of maternal levels; hydrochlorothiazide readily crosses the placenta. |
| Breastfeeding |
■ FDA Black Box Warning
No FDA boxed warning for LOREEV XR. The immediate-release formulation carries no black box warning; however, levetiracetam is associated with suicidal behavior and ideation, but this is not classified as a black box warning for LOREEV XR.
| Serious Effects |
Hypersensitivity to labetalol, hydrochlorothiazide, or sulfonamide-derived drugsBronchial asthmaSinus bradycardiaSecond- or third-degree AV blockCardiogenic shockAnuriaSevere renal impairment (CrCl <30 mL/min)
| Precautions | Suicidal behavior and ideation: Monitor for depression and suicidality, Behavioral and psychiatric adverse reactions: Psychosis, aggression, irritability, Somnolence and dizziness: Caution with activities requiring alertness, Hematologic abnormalities: Decreased red blood cell counts, leukopenia, neutropenia, pancytopenia, Dermatologic reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis (rare), Withdrawal seizures: Do not discontinue abruptly; taper dose gradually, Renal impairment: Dose adjustment required in patients with decreased renal function |
| Food/Dietary |
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| Labetalol is excreted into breast milk in small amounts; however, adverse effects in infants are rare. Hydrochlorothiazide is also excreted in breast milk and may suppress lactation due to diuresis. Use with caution, particularly in premature or renally impaired infants. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Increased risk of neural tube defects and other congenital anomalies based on animal studies and limited human data. Second and third trimesters: Potential for fetal malformations and adverse effects on fetal growth and development. Placental transfer is likely. |
| Fetal Monitoring | Monitor maternal liver function, renal function, and complete blood counts. Fetal ultrasound to assess growth and anatomy. Nonstress test or biophysical profile in third trimester if indicated. |
| Fertility Effects | May impair female fertility based on animal studies showing effects on estrous cycle and ovarian function. Reversibility in humans unknown. |
| Avoid grapefruit and grapefruit juice; may increase codeine levels. Take with food if GI upset occurs. Avoid high-fat meals as they may delay absorption. |
| Clinical Pearls | LOREEV XR is a combination of codeine and promethazine. Caution: respiratory depression risk, especially in children, obese, or with sleep apnea. Avoid in breastfeeding; codeine is metabolized to morphine and may cause infant toxicity. Use lowest effective dose for shortest duration. |
| Patient Advice | Take exactly as prescribed; do not increase dose or frequency. · Avoid alcohol and other CNS depressants. · Do not drive or operate machinery until you know how the drug affects you. · Store securely out of reach of children; improper use can cause overdose and death. · Stop use and seek medical help if you have slow or shallow breathing, confusion, or severe drowsiness. · If pregnant, planning to become pregnant, or breastfeeding, consult your doctor before use. |